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Clin Genitourin Cancer. 2018 Aug;16(4):266-273. doi: 10.1016/j.clgc.2018.01.013. Epub 2018 Feb 5.

Polymorphisms in the Von Hippel-Lindau Gene Are Associated With Overall Survival in Metastatic Clear-Cell Renal-Cell Carcinoma Patients Treated With VEGFR Tyrosine Kinase Inhibitors.

Author information

1
Laboratory of Experimental Oncology, Department of Oncology, University of Leuven, Leuven, Belgium; Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium.
2
Center for Cancer Biology, Flemish Institute for Biotechnology, Leuven, Belgium; Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven, Belgium.
3
INSERM, UMR-1162, Functional Genomics of Solid Tumors, Institute of Hematology, Paris, France.
4
Laboratory of Experimental Oncology, Department of Oncology, University of Leuven, Leuven, Belgium.
5
Department of Urology, University Hospitalsof Central Paris, Paris, France.
6
Department of Pathology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium.
7
Department of Medical Oncology, University Hospitalsof Central Paris, Paris, France.
8
Department of Pathology, University Hospitalsof Central Paris, Paris, France.
9
Programme Cartes d'Identité des Tumeurs, Ligue Nationale Contre le Cancer, Paris, France.
10
Institut Roi Albert II, Service d'Oncologie Médicale, Cliniques universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale, Université Catholique de Louvain, Brussels, Belgium.
11
Department of Urology, Hôpital Bicêtre, Paris, France.
12
Laboratory of Experimental Oncology, Department of Oncology, University of Leuven, Leuven, Belgium; Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium. Electronic address: benoit.beuselinck@uzleuven.be.

Abstract

BACKGROUND:

Clear-cell renal-cell carcinoma (ccRCC) is characterized by loss of a functional Von Hippel-Lindau (VHL) protein. We investigated the potential of 3 single nucleotide polymorphisms (SNPs) in VHL as biomarkers in metastatic ccRCC (m-ccRCC) patients treated with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs).

PATIENTS AND METHODS:

We genotyped 3 VHL SNPs in 199 m-ccRCC patients: rs1642742 T > C, rs1642743 A > G, and rs1678607 C > A. Primary end points were response rate (RR), progression-free survival (PFS), and overall survival (OS) after start of first-line TKI. RR was compared with Fisher's exact test, and PFS and OS with Kaplan-Meier analysis and multivariable Cox regression. Secondary end points were association with VHL promotor hypermethylation, VHL mutation status, VHL loss of heterozygosity, ≥ 25% sarcomatoid dedifferentiation, and expression of genes implicated in angiogenesis and immunoresponse (Fisher's exact test and unpaired t tests).

RESULTS:

The minor alleles of rs1642742 and rs1642743, known to be in close linkage disequilibrium, were associated with poor outcome, following a recessive pattern. For the rs1642742 CC versus TT/TC genotype, OS was 11 versus 26 months (hazard ratio = 2.3; 95% confidence interval, 1.2-6.6; P = .015). For the rs1642743 GG versus AA/AG genotype, OS was 15 versus 28 months (hazard ratio = 2.6; 95% confidence interval, 1.4-5.0; P = .004). After multivariable analysis, both remained linked with poor OS (P = .018 and P = .009, respectively). There was a trend toward shorter PFS and poorer RR. Both SNPs were associated with ≥ 25% sarcomatoid dedifferentiation (P = .037 and .006, respectively). No significant results were found for rs1678607.

CONCLUSION:

rs1642742 and rs1642743 are candidate biomarkers for poor OS in m-ccRCC patients receiving first-line VEGFR-TKI. They are associated with higher levels of sarcomatoid dedifferentiation.

KEYWORDS:

Biomarker; SNP; Sarcomatoid dedifferentiation; rs1642742; rs1678607

PMID:
29503246
DOI:
10.1016/j.clgc.2018.01.013
[Indexed for MEDLINE]

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